The nucleus accumbens (NAc) is a critical brain area involved in motivation and mediates the rewarding and addictive properties of several classes of abused drugs. Additionally, because of its role in motivational processes, the NAc is also implicated in psychiatric disorders that involve alterations in mood, motivation. Therefore, it is necessary to understand the basic function of this brain region, as well as the actions of abused drugs such as marijuana, cocaine, opioids, and designer drugs on this system. The NAc is largely comprised of medium spiny, GABAergic output neurons (MSNs) that receive innervation from other MSNs, glutamate innervation from many additional brain areas, and dopamine innervation from the ventral midbrain. Acutely, both GABA and glutamate synapses onto MSNs are inhibited by several classes of abused drugs, suggesting that this action may contribute to their rewarding properties, and long-term exposure to drugs alters the function of both intrinsic circuits and extrinsic inputs. In addition, abused drugs are known to increase the release of dopamine (DA)in the NAc, and this likely contributes to long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. Although much is known about the contributions of the NAc to behavior, the precise mechanisms in which such synaptic plasticity contributes to behavior, and how abused drugs alter synaptic processes remains poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing electrophysiological and fast scan cyclic voltammetry (FSCV) recording combined with optogentic techniques in brain slices obrained from transgenic and normal rodents. By combining these approaches, we can simultaneously monitor changes in DA levels and the development of synaptic plasticity. Current experiments involve examining the synaptic properties of excitatory synapses onto NAc MSNs arising from ventral tegmental (VTA)DA neurons in transgenic rats in which cre recombinase is under control of the tyrosine hydroxylase promoter (TH-Cre rats). This permits selective expression of the light-activated proteins, such as channelrhodopsin-2 (ChR-2), when an adeno-associated virus containing the ChR-2 construct (AAV-DIO-ChR2) is used. As many tyrosine hydroxylase positive (TH+) VTA neurons also express the vesicular glutamate-2 transporter (VGlut-2) they are capable of co-transmitting DA and glutamate signals to the NAc. Confirming this, we find that light-activation of ChR2 evokes glutamate-mediated synaptic EPSCs in the NAc shell following virus injections into the VTA. These EPSP properties are then compared to those evoked by ChR2 injected into other pathways targeting the NAc, such as the ventral hippocampus, basolateral amygdala and medial prefrontal cortex. We find that the magnitude of glutamate innervation of the NAc arising from these inputs varies widely, and that the biophysical properties of these inputs are distinguishable. We also find that long-term exposure to the psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC) differentially alters the strength of these NAc inputs, as well as their capacity to generate synaptic plasticity. Specifically, exposure to THC over a 2 week period causes a significant weakening of prefrontal inputs to the NAc shell, and greatly strengthens inputs arising from the ventral hippocampus and basolateral amygdala. Interestingly, although the overall strength of glutamate input to the NAc arising from VTA is not changed, the biophysical properties of this pathway are altered in a way that suggests that homeostatic compensation occurs. The pattern of changes observed in the inputs to the NAc are consistent with those reported in brain imaging studies conducted in human marijuana users, and suggest a loss of cortical control over the NAc with chronic THC use. This has important implications for cognition and emotional processing that is also consistent with behavioral changes seen in humans. Therefore, we hypothesize that the changes we have identified are related to behavioral and psychiatric changes seen in humans that are diagnosed with cannabis use disorder.